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Review
, 5 (8), a012724

DNA Damage Response: Three Levels of DNA Repair Regulation

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Review

DNA Damage Response: Three Levels of DNA Repair Regulation

Bianca M Sirbu et al. Cold Spring Harb Perspect Biol.

Abstract

Genome integrity is challenged by DNA damage from both endogenous and environmental sources. This damage must be repaired to allow both RNA and DNA polymerases to accurately read and duplicate the information in the genome. Multiple repair enzymes scan the DNA for problems, remove the offending damage, and restore the DNA duplex. These repair mechanisms are regulated by DNA damage response kinases including DNA-PKcs, ATM, and ATR that are activated at DNA lesions. These kinases improve the efficiency of DNA repair by phosphorylating repair proteins to modify their activities, by initiating a complex series of changes in the local chromatin structure near the damage site, and by altering the overall cellular environment to make it more conducive to repair. In this review, we focus on these three levels of regulation to illustrate how the DNA damage kinases promote efficient repair to maintain genome integrity and prevent disease.

Figures

Figure 1.
Figure 1.
DDR kinases promote efficient DNA repair by directly regulating the DNA repair machinery, changing the local chromatin environment near the DNA lesion, and altering the cellular environment.
Figure 2.
Figure 2.
A simplified model of ICL repair indicating steps regulated by ATR phosphorylation.
Figure 3.
Figure 3.
DDR kinases regulate the chromatin near a double-strand break to provide a scaffold for the recruitment of DNA repair proteins, promote repair protein access through nucleosome remodeling, and inhibit local transcription.
Figure 4.
Figure 4.
DDR kinases regulate several aspects of nuclear and cellular physiology to provide an environment conducive for successful DNA repair.

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